DESCRIPTION (Applicant's Abstract): The applicant's ultimate career goal is to combine research and clinical practice in an academic setting where she also will be able to participate in the training of residents and medical students. This proposal, which will serve as her dissertation, focuses on the host immune response to intracerebral mesencephalic grafts in an animal model of Parkinson's disease. Skills she will learn in the course of training include stereotaxic surgery, fetal brain dissection, neuronal cell culture, in situ hybridization, immunohistochemistry, 6-OHDA lesioning, behavioral measurements, and proper design and interpretation of experiments. These skills, along with the multidisciplinary training offered in the Neuroscience Department, will provide a foundation for her development as a clinical research scientist with interests in neuroimmunomodulation and neuroendocrine-immune interactions. In addition, this project is suited to her career goals in that she will learn these specific skills in the process of conducting a project with clinical relevance. In terms of the project itself, low cell survival confounds efforts to utilize fetal tissue transplantation as a replacement therapy in human diseases, such as Parkinson's Disease. The death of neurons in developing ventral mesencephalic grafts was assumed to be necrotic until recent efforts revealed that these cells also undergo apoptoic death. Immune-mediated rejection of intracerebral transplants may impede significantly the survival of histoincompatible grafts; in fact, rejection has been demonstrated in rodent and non-human primate transplantation paradigms. Since alloreactive cytoxoxic T cells are important in peripheral graft rejection and can induce apoptotic death in their target cells, this proposal will attempt to: 1) determine whether allogeneic lymphocytes contribute to apoptotic death of mesencephalic cells in a co-culture model, 2) characterize and quantify immune cell populations recruited to the area of the graft in vivo, and 3) to determine whether lymphocytes in and around the graft lead to increased apoptotic death of grafted cells. Since the host's immune response may contribute to the death of transplanted neurons, utilization of knowledge gained in detailed studies of this response ultimately may lead to means by which survival can be increased. The applicant's long term objectives are to assess the contribution of the host immune response to the death of mesencephalic neurons in an effort to gain a greater understanding as to whether immunosuppression is necessary in neural transplantation.